Low-Dose Lithium for the Treatment of Behavioral Symptoms in Frontotemporal Dementia

Behavioral symptoms of Frontotemporal dementia (FTD), including agitation, aggression, and
inappropriate repetitive behaviors are common, distressing to patients and caregivers, often
lead to institutionalization, and can be very difficult and expensive to treat. There is a
dearth of medication for treating these symptoms in FTD. Typically, antidepressants and
antipsychotic medications are prescribed - which low efficacy and, with the latter class,
carry serious adverse effects such as parkinsonism and increased cardiovascular-related
mortality. The investigators propose a study of the efficacy of lithium carbonate compared
to placebo in the treatment of agitation, aggression, and inappropriate repetitive behaviors
in 60 patients with FTD in a randomized, double-blind, two-arm parallel 12-week trial.
Lithium is a highly effective treatment for mania and symptoms of agitation or aggression in
bipolar disorder. It also inhibits tau aggregation and phosphorylation, leading to
considerable interest in its use as a disease-modifying treatment for tauopathies such as
FTD and Alzheimer's disease. Unfortunately, earlier trials using typical doses (i.e., doses
prescribed for treatment of bipolar disorder) showed high incidence of serious adverse
effects (including confusion and delirium). For the study proposed study the investigators
will: 1) use lower doses and lower target serum concentrations than have preceding trials
(shown in preliminary data from a Columbia study and data from other labs to be
well-tolerated) and 2) target behavioral symptoms rather than cognitive outcomes.

Inclusion Criteria:

- Age 40-85

- A diagnosis of behavioral variant FTD (bv-FTD) or semantic variant Primary
Progressive Aphasia (sv-PPA, which is generally accompanied by a behavioral
syndrome), or agrammatic/non-fluent Primary Progressive Aphasia (nfv-PPA) with
behavioral symptoms

- Neuropsychiatric Inventory (NPI) agitation/aggression subscale score ≥4 or
disinhibition subscale score ≥ 4 or repetitive behavior subscale ≥ 4 or total score ≥
6. On each subscale, a score higher than 4 represents moderate to severe symptoms

- Folstein Mini-Mental State Examination (MMSE) score 5-26/30

- An study partner (usually a family member) is required to provide information during
interviews about the patient

- Capacity to consent. Subjects without capacity to consent must have capacity to
appoint a surrogate

- Structural MRI or CT scan after symptom onset

Exclusion Criteria:

- Medical contraindication or history of intolerability to lithium, falls in the last
month, current abnormal thyroid functions (T3, T4 or thyroid stimulating hormone
(TSH); treated hypothyroidism with normal thyroid function tests will not lead to
exclusion), creatinine level > 1.5 mg/100 ml or glomerular filtration rate < 44
ml/min/1.73m2 will also lead to exclusion

- The diagnosis of bipolar disorder or schizophrenia or schizoaffective disorder

- Alcohol or substance use disorder in the prior 6 months

- Current diagnosis of other major neurological disorder, e.g., Alzheimer's Disease
(AD), stroke with residual clinical deficits, multiple sclerosis, Parkinson's
disease. Subjects with MRI or CT evidence of cerebrovascular disease but without
clinical signs of stroke will be included

- Sitting blood pressure > 150/90 mm Hg, unstable cardiac disease, severe or unstable
medical illness

- Use of medications, including diuretics, known to have adverse effects when combined
with lithium. Use of antipsychotic medications will be permitted

- Current major depression or suicidality or dangerous behavior with risk of harm to
self and others

- Corrected QT interval (QTc) interval > 460 ms at the time of baseline
electrocardiogram (EKG)

- Woman of child-bearing potential